1. Field of the Invention
This invention relates to the field of diagnosis and treatment of bipolar affective disorders.
2. Background
The most characteristic features of bipolar affective disorder (manic-depressive illness) are episodes of mania (bipolar I, BPI) or hypomania (bipolar II, BPII) that are interspersed with periods of depression. If untreated, manic-depressive illness is associated with an approximately 20% risk of suicide. Even with treatment, this disorder constitutes a major public health problem, afflicting approximately one percent of the population. Goodwin et al., Manic-Depressive Illness (Oxford University Press, New York, 1990).
Although little is known about the etiology or pathophysiology of bipolar affective disorder, genetic and environmental factors contribute to its pathogenesis, especially in families with multiple affected members. Considerable genetic and epidemiologic data derived from twin, family and adoption studies provide compelling evidence for a genetic etiology of this disorder, but the mode(s) of inheritance has not been identified. Craddock et al., Ann. Med. 25:317-322 (1993). Nonetheless, to date, the majority of genetic linkage studies of bipolar affective disorder have assumed that it exhibits classical Mendelian inheritance attributable to a single major gene. Segregation analyses have yielded inconsistent results with most studies rejecting a single dominant or recessive locus inheritance model. However, if only BPI is considered, the best single gene model is dominant inheritance. Pauls et al., Neuropsy. Genet., 60:290-297 (1995).
Due to the complexities inherent in linkage studies of psychiatric disorders, one study has focused on the identification of a gene for bipolar illness in a large Old Order Amish pedigree in southeastern Pennsylvania. Egeland et al., Nature, 325:783-787 (1987). The Old Order Amish are a religious sect numbering approximately 15,000 who descend from some 30 pioneer couples and who have remained genetically isolated, thereby minimizing the introduction of multiple genes responsible for inherited disorders. Amish families have large sibships and multiple living generations, making them ideal for genetic studies. Further, alcohol and drug abuse, which often complicate psychiatric diagnoses, are rare among the Amish. Bipolar affective disorder, however, occurs amongst the Old Order Amish with a prevalence rate, characteristic symptom pattern and clinical course that are similar to those in the general North American population. The identification and characterization of these pedigrees led to the initiation of early genetic linkage studies but no evidence for linkage between various polymorphic serum proteins or blood group antigen loci and affective disorder was found.
More recently, using a molecular genetic approach, Egeland and colleagues reported evidence supporting the localization of a gene conferring a strong predisposition to bipolar affective disorder linked to two loci located on the short arm of chromosome 11, the Harvey-ras-1 oncogene locus (HRAS) and the insulin (INS) locus. Id. However, reanalysis of the Old Order Amish pedigree to include several new individuals, two changes in clinical status, and a large lateral extension of the original pedigree markedly reduced the probability of linkage between bipolar affective disorder and the HRAS and INS loci. Kelsoe et al., Nature, 342:238-243 (1989).
Attempts to replicate linkage findings for bipolar affective disorder have proven problematic and have been plagued by diagnostic uncertainties, genetic heterogeneity, phenocopies, genotyping errors, and the complexities of performing and interpreting statistical analyses (Egeland et al. (1987) Nature 325, 783-787; Pekkarinen et al. (1995) Genome Res. 5: 105-115; Ginns et al. (1996) Nature Genet. 12, 431-435; NIMH Genetics Initiative Bipolar Group (1997) Am. J. of Med. Genetics (Neuropsych. Genetics) 74, 227-269; Blackwood et al. (1996) Nature Genet. 12, 427-430; Freimer et al. (1996) Nature Genet. 12, 436-441). Reported linkages of bipolar affective disorder to DNA markers on chromosomes 18, 21 and X have been difficult to replicate and several proposed linkages have been refuted upon reanalysis. Kelsoe et al., Nature, 342:238-243 (1989), Berrettini et al., Proc. Natl. Acad. Sci. USA, 91:5918-5921 (1994), Straub et al., Nature Gen. 8:291-296 (1994), Baron et al., Nat. Genet., 3:49-55 (1993), Pauls et al., Am. J. Hum. Genet., 57:636-643 (1995).
Moreover, since the inheritance of BPAD is probably multifactorial, the possible involvement of multiple genetic components of small effect and/or the occurrence of major allelic effects only in epistasis must be considered. In addition to susceptibility alleles, there could be alleles that reduce the risk of developing BPAD in a manner similar to that reported for other complex genetic disorders (Philibert et al. (1997) J. Affective Disorders 43, 1-3). If model-based linkage analyses are used, a “false negative” linkage finding could result when individuals inherit disease susceptibility alleles but do not manifest the phenotype due to the presence of “protective” alleles. The inclusion of individuals who inherit susceptibility alleles but do not manifest disease because of “protective” alleles, or of individuals who inherit “protective” alleles but nevertheless manifest the disease, will also reduce the power of model-free (allele-sharing) analyses. Thus, regardless of whether model-based or model-free analyses are used, “wellness” or “protective” alleles could have a significant impact on linkage analyses.
Given the magnitude of the public health problem associated with bipolar illness and the availability of treatments for this disorder, what is needed in the art is a means to determine the risk to an individual, who comes from an affected family, of developing bipolar affective disorder. Given that risk can depend both on susceptibility and protective alleles, it is desirable to have means to determine the presence or absence of both types of alleles associated with bipolar affective disorder. Quite surprisingly, the present invention provides these and other advantages.